SUMMARY Exciting clinical breakthroughs with checkpoint blockade antibodies and adoptive T cell transfers have transformed the field of cancer immunotherapy, demonstrating the power of harnessing the immune system to eliminate cancer cells. However, fundamental challenges and questions remain. Significant clinical responses have only been observed in a subset of patients and cancer types, and it is currently not known what biological properties of tumors determine clinical responses, nor what strategies to adopt in clinical contexts where current immunotherapies are ineffective. To ultimately address these clinical challenges and to design predictably effective cancer treatments, we must deepen our fundamental understanding of interactions between tumors and the immune system at the molecular, cellular, and systems levels. The CSBC Research Center for Cancer Systems Immunology at MSKCC will bring the tools of systems biology to investigate cancer-immune system interactions at multiple stages of disease progression to answer central questions in cancer immunology and inform the design of novel immunotherapeutic interventions. We have organized our Research Center around three central scientific projects that examine cancer-immune interactions at distinct stages of disease progression: cancer initiation and early tumorigenesis (Project I); established and progressing tumors (Project II); latent disease and metastasis in (Project III). In Project I, we will combine new epigenomics technologies and innovative single-cell analyses with state-of-the-art systems biology approaches to decipher the underlying molecular and epigenetic programs of dysfunctional tumor- specific T cell differentiation in early tumorigenesis. We will further elucidate how dynamics in the mutational tumor antigen landscape and stromal and immune cell populations determine such states and model and test in mouse and human tumors how distinct T cell states determine sensitivity to immune checkpoint blockade. In Project II, we will use quantitative analysis of cell types and cell states by functional, flow cytometric, population RNA-seq and droplet RNA sequencing together with ecological models of cancer, immune, and stromal cell populations to study the response of the tumor ecosystem to immunotherapeutic perturbations in established tumors. In Project III, we will examine the evolutionary dynamics of innate immune system control of metastatic disease, a new area of investigation in cancer immunology. We will investigate the heterogeneity of latent cancer cells in their capacity for immune evasion, and we will use quantitative methods, including live cell imaging, to model latent tumor cell evasion of innate immune control and the dynamics of cycles of latent cell proliferation and potential editing by NK cells. A Shared Resource Core will provide state-of-the-art single-cell droplet sequencing technology and computational analysis of single-cell RNA-seq data (scRNA- seq). This Shared Resource Core will be tasked with droplet sequencing technology development and design of novel algorithmic approaches and will interact with all three scientific Projects. Our Research Center will also carry out an innovative program of outreach and training activities at the local, national, and global levels to disseminate research findings in cancer systems immunology and to train young scientists in this emerging field.